1. Field of the Invention
This invention relates to the treatment of certain central and peripheral nervous system disorders by inhibition of the glycine transporter 2. The invention relates in particular to the use of a group of compounds in the treatment in humans of certain neurological disorders, for example, psychoses, pain, epilepsy, neurodegenerative diseases, stroke, head trauma, multiple sclerosis and the like. The invention also relates to a group of novel compounds and pharmaceutical compositions containing them which are useful in inhibition of the glycine transporter 2.
2. Description of Related Art
Synaptic transmission is a complex form of intercellular communication that involves a considerable array of specialized structures in both the pre- and post-synaptic neuron. High affinity neurotransmitter transporters are one such component, located on the pre-synaptic terminal membranes and surrounding glial cells (Kanner and Schuldiner, CRC Critical Reviews in Biochemistry, 22, 1032 (1987)). Transporters sequester neurotransmitter from the synapse, thereby regulating the concentration of neurotransmitter in the synapse, as well as its duration of action therein, which together influence the magnitude and duration of synaptic transmission. By preventing the spread of transmitter to neighboring synapses, transporters help maintain the fidelity of synaptic transmission. In addition, by sequestering released transmitter into the presynaptic terminal, transporters allow for transmitter reutilization.
The amino acid glycine is a major neurotransmitter in the mammalian central nervous system (CNS), functioning at both inhibitory and excitatory synapses. These distinct functions of glycine are mediated by two different types of receptor, each of which is associated with a different class of glycine transporter. The inhibitory actions of glycine are mediated by glycine receptors that are sensitive to the convulsant alkaloid strychnine, and are referred to “strychnine-sensitive.” Such receptors contain an intrinsic chloride channel that is opened upon binding of glycine to the receptor; by increasing chloride conductance, the threshold for firing of an action potential is increased. Strychnine-sensitive glycine receptors are found predominantly in the spinal cord and brainstem, and pharmacological agents that enhance the activation of such receptors will thus increase inhibitory neurotransmission in these regions. For example, enhancing inhibitory glycinergic transmission through strychnine-sensitive glycine receptors in the spinal cord can be used to decrease muscle hyperactivity. In addition, pain-related information in the spinal cord has been shown to be mediated by these receptors (Yaksh, Pain, 37, 111 (1989)).
Nucleic acid sequences and transfection techniques for delivering nucleic acid message coding for glycine transporters are disclosed in U.S. Pat. No. 5,756,348, U.S. Pat. No. 6,127,131, U.S. Pat. No. 5,824,486, U.S. Pat. No. 5,968,823, and U.S. Pat. No. 6,008,015. Molecular cloning has revealed the existence in mammalian brains of two classes of glycine transporters, termed GlyT1 and GlyT2. GlyT1 is found predominantly in the forebrain, and its distribution corresponds to that of glutaminergic pathways and NMDA receptors (Smith et al., Neuron, 8, 927 (1992)). Additional cloning experiments has determined that GlyT1 transporter has three additional variants, GlyT1a, GlyT1b, and GlyT1c. GlyT2 is found predominantly in the brain stem and spinal cord, and its distribution corresponds closely to that of strychnine-sensitive glycine receptors. This is consistent with the view that by regulating the synaptic levels of glycine, GlyT1 and GlyT2 selectively influence the activity of the NMDA receptors and strychnine-sensitive glycine receptors, respectively.
Triazoles, oxadiazoles, and thiadiazoles are known in the art. They have shown a wide variety of uses in photographic material (JP 09-114055, JP 07-005646) and in liquid crystal compositions (JP 11-043485). These types of heterocyclic derivatives have also been reported as pesticides, fungicides and herbicides (JP 10-036357, JP 05-202038, JP 02-129173, DE 3717865, DE 3031191, DE 2533605). There are a number of highly functionalized analogs showing activity as immunosuppressants, antiinflammatories and hepatoprotectants (U.S. Pat. No. 5,670,526, EP 214732), Gp IIb/IIIa antagonists (U.S. Pat. No. 5,668,159), antiulcer (WO 95/13268) and as angiotensin II antagonists (EP 554107, WO 91/11909, EP 409332).
Substituted triazoles have been reported to be neurotensin antagonists and be useful in the treatment of certain CNS and gastrointestinal disorders (GB 2263635, WO 98/30561). Recently, there have been some reports of piperidinyl-, and piperazinyl-triazoles as inhibitors of the glycine transporters (WO 99/45011, WO 99/44596); and diarylglycine derivatives have been shown to inhibit GlyT1 and GlyT2 (WO 97/45115).
The documents cited here and elsewhere in this application are incorporated herein by reference in their entirety.